Tenidap, presently shown as the enolic form of 5-chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-indole-1-carboxamide, has the structural formula ##STR1## Tenidap and the pharmaceutically-acceptable base salts thereof, among other 3-substituted-2-oxindole-1-carboxamides, are disclosed and claimed in U.S. 4,556,672 which is assigned to the assignee hereof. That patent discloses that those compounds, in addition to being useful as anti-inflammatory and analgesic agents, are inhibitors of both the cyclooxygenase (CO) and lipoxygenase (LO) enzymes. The teachings thereof are incorporated herein by reference.
The use of tenidap and its pharmaceutically-acceptable base salts, among certain other 3-substituted-2-oxindole-l-carboxamides, to inhibit interleukin-1 biosynthesis in a mammal and to treat interleukin-1 mediated disorders and dysfunctions is disclosed in U.S. 4,861,794 which is assigned to the assignee hereof.
U.S. 4,853,409, assigned to the assignee hereof, discloses the use of tenidap and its pharmaceutically-acceptable base salts, among certain other 3-substituted-2-oxindole-l-carboxamides, to suppress T-cell function in a mammal and to treat T-cell mediated autoimmune disorders of the systemic or organ specific type.
An anhydrous, crystalline form of the sodium salt of tenidap is disclosed in European Patent Application 277,738 which has been filed in the name of the assignee hereof.
U.S. 5,008,283, assigned to the assignee hereof, discloses the use of tenidap and its pharmaceutically-acceptable base salts to inhibit activation of collagenase, treat collagenase mediated disorders and diseases and inhibit the activity of myeloperoxidase in a mammal.
U.S. 5,006,547, assigned to the assignee hereof, discloses the use of tenidap and its pharmaceutically-acceptable base salts to inhibit the release of elastase by neutrophils in a mammal and to treat elastase-mediated diseases and dysfunctions in a mammal.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the U.S. and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease has been described in detail by Ross and Glomset in New England Journal of Medicine 295, 369-377 (1976). The earliest stage in this sequence is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Cholesterol and cholesteryl ester account for most of this lipid. Further, it is postulated that most of the cholesterol found within the fatty streaks results from uptake from the plasma. These fatty streaks, in turn, give rise to development of the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the "complicated lesion" which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscular spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma triglyceride levels, cholesterol levels, and low density lipoprotein cholesterol levels in particular, as essential steps in prevention of CVD. The upper limits of "normal" are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at high risk for development or progression of CVD because of this factor. Individuals who possess independent risk factors in addition to hyperlipidemia are at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Successful treatment of hyperlipidemia in the general population is therefore of exceptional medical importance.
The first step in recommended therapeutic regimens for hyperlipidemia is dietary intervention. While diet alone produces adequate response in some individuals, many others remain at high risk and must be treated further by pharmacological means. New drugs for the treatment of hyperlipidemia are, therefore, of great potential benefit for large numbers of individuals at high risk of developing CVD.
Until the invention herein, there was no report of use or intent to use tenidap or the salts thereof to reduce total serum cholesterol levels, to reduce serum LDL cholesterol levels or to reduce serum triglycerides in a mammal.